De Novo Sirolimus and Reduced-Dose Tacrolimus Versus Standard-Dose Tacrolimus After Liver Transplantation: The 2000–2003 Phase II Prospective Randomized Trial

Abstract

We studied whether the use of sirolimus with reduceddose tacrolimus, as compared to standard-dose tacrolimus, after liver transplantation is safe, tolerated and efficacious. In an international multicenter, open-label, active-controlled randomized trial (2000)(2001)(2002)(2003), adult primary liver transplant recipients (n ¼ 222) were randomly assigned immediately after transplantation to conventional-dose tacrolimus (trough: 7-15 ng/mL) or sirolimus (loading dose: 15 mg, initial dose: 5 mg titrated to a trough of 4-11 ng/mL) and reduced-dose tacrolimus (trough: 3-7 ng/mL). The study was terminated after 21 months due to imbalance in adverse events. The 24-month cumulative incidence of graft loss (26.4% vs. 12.5%, p ¼ 0.009) and patient death (20% vs. 8%, p ¼ 0.010) was higher in subjects receiving sirolimus. A numerically higher rate of hepatic artery thrombosis/portal vein thrombosis was observed in the sirolimus arm (8% vs. 3%, p ¼ 0.065). The incidence of sepsis was higher in the sirolimus arm (20.4% vs. 7.2%, p ¼ 0.006). Rates of acute cellular rejection were similar between the two groups. Early use of sirolimus using a loading dose followed by maintenance doses and reduced-dose tacrolimus in de novo liver transplant recipients is associated with higher rates of graft loss, death and sepsis when compared to the use of conventional-dose tacrolimus alone.

Review on immunosuppression in liver transplantation

“…Maintenance of immunosuppression Starting 10-15 mg/kg per day divided every 12 h and adjust to the desired (C2) level Mycophenolate mofetil (Cellcept ® , Myfortic ® ) [60] Anti-metabolite Maintenance of immunosuppression, treatment of rejection Variable doses may be desired in any individual case Azathioprine (Imuran ® ) [65] Anti-metabolite Maintenance of immunosuppression Variable, maintenance dose may be 1.5-2.5 mg/kg per day, needs to be adjusted for adverse side effects Sirolimus (Rapamune ® ) [48,68,71] [44][45][46] T cell depleting monoclonal antibody…”

“…No specific renal improvement benefit by CNI to sirolimus conversion was also demonstrated in another study by Abdelmalek et al [67] , while higher biopsy proven rejections and treatment associated adverse side effects were seen in the sirolimus group. Even de novo use of sirolimus with low dose tacrolimus resulted in a high rate of graft loss, death and sepsis when compared with conventional tacrolimus dose, leading to the premature termination of a prospective randomized trial by Asrani et al [68] . Everolimus is another mTORI that when introduced early post LT and combined with low dose tacrolimus, showed promising results with respect to rejection rates and significant beneficial effects on renal function after 2 years [69] .…”

Strategies to improve outcome of patients with hepatocellular carcinoma receiving a liver transplantation

“…The major concern with sirolimus relies in its safety profile. A large phase Ⅱ randomized trial (n = 222) evaluated de novo sirolimus and reduced tacrolimus after liver transplantation compared with a control arm composed by conventional tacrolimus [133] . The study had to be prematurely stopped due to an imbalance of adverse outcomes between groups.…”

Everolimus is safe within the first month after liver transplantation

“…In LT patients mTOR inhibitors are often used to minimize the exposure to calcineurin inhibitors in order to avoid their adverse effects, particularly renal impairment and long-term malignancy. In the sirolimus phase II trial a conventional tacrolimus arm was compared with de novo sirolimus and reduced tacrolimus [2]. The study had to be prematurely stopped due to an increased risk of sepsis, graft loss and mortality at 24 months in the sirolimus arm.…”